Process for the preparation of citalopram

Abstract

The present invention provides, inter alia, a novel process for the preparation of Citalopram, a known antidepressant.

Description

CROSS-REFERENCE TO RELATED APPLICATION [0001] The present application claims priority to U.S. Provisional Patent Application No. 60 / 324,821, filed Sep. 24, 2001, the teachings of which are incorporated herein by reference for all purposes.BACKGROUND OF THE INVENTION [0002] Citalopram is an antidepressant drug that is widely used in both the United States and Europe. Its mode of action and activity have been described in various publications. The active ingredient is an HBr or oxalate salt, preferably an HBr salt. Citalopram has the following structure: [0003] Several processes have been described in the literature for preparing Citalopram (see, Drugs of Future, 25(6):620 (2000). Citalopram was first disclosed in German Patent 2,657,271, which is the German equivalent of now expired U.S. Pat. No. 4,136,193. In this patent, 5-bromophthalide (5-BP) was converted via a five-step reaction sequence to Citalopram. This route for preparing Citalopram is depicted in FIG. 1, and constitutes ...

AI Technical Summary

Benefits of technology

[0032] The present invention provides a novel process for the preparation of Citaopram and, in particular, Citalopram.HBr. Using the process of the present invention, Citalopram.HBr can be readily prepared in high yields, at the quality specifications required for use in pharmaceutical applications (i.e., greater than 99.7% pure) and without the limitations of the prior art methods.

Problems solved by technology

Attempts to reproduce the process described in U.S. Pat. No. 4,136,193 for the preparation of Citalopram in the quality specifications required for its use in pharmaceutical applications have been unsuccessful.

Difficulty encountered in manufacturing Citalopram of the required purity by the process described in German Patent No. 2,657,013, U.S. Pat. No. 4,136,193 and PCT International Publication Nos.

Unfortunately, the work-up is very complex and involves excessive handling of a flammable liquid, i.e., diethyl ether.

The above work-up process is very laborious and is not suited for large-scale production.

Again, it involves the excessive handling of flammable solvents, such as diethyl ether, and it involves numerous unit operations, thereby reducing productivity.

Since Br-Diol is an oil, it cannot be isolated as a crystalline solid and, thus, it cannot be purified by techniques such as crystallization / recrystallization.

It is believed that this is one of the major reasons why the process described in U.S. Pat. No. 4,136,193 fails to provide Citalopram in the quality, i.e., purity, required for drug applications.

This is troublesome because on reaction completion excess phosphoric acid has to be neutralized with ammonia.

Neutralization is an extremely exothermic process and heat management becomes a major issue in the commercial-scale production of this material.

In addition, the use of such a large excess of phosphoric acid increases the cost of commercial scale operations due to the use of excess reagents, longer cycle times and reduced loading.

Moreover, from a safety point of view, the use of flammable solvents, such as diethyl ether, is discouraged for the commercial-scale production of organic compounds.

Unfortunately, there are numerous problems with step four.

Removal 5 of unreacted 5-Br is difficult and normal purification techniques, such as extraction, crystallization, etc., are not effective.

In short, the process described in U.S. Pat. No. 4,136,193 does not work to provide acceptable quality Citalopram.

Moreover, the work-up is laborious and involves the use of undesirable solvents such as benzene and diethyl ether.

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